This invention relates to sustained release pharmaceutical preparations capable of releasing active ingredients sustainedly and in a pulse-like manner. More particularly, the invention relates to sustained release pharmaceutical preparations designed so that active ingredients which are desirably released pulsewise, such as biologically-active trace substances [e.g. peptide protein type active substances (e.g. hormones, cytokines), postaglandins, steroids, vitamins and the like], other active trace substances, anticancer agents and antibiotics, can be released therefrom in a pulse-like and clinically significant manner and thereby the pharmacological effects of said active ingredients can be maintained for a prolonged period of time.
Hithertofore various dosage forms and systems have been designed in an attempt to attain sustained release of drugs in a manner such that the drug concentrations can be maintained at clinical therapeutic levels. They bring sustained release to many kinds of drugs. However, as far as biologically-active trace substances, such as peptide protein type active substances (e.g. hormones, cytokines), prostaglandins, steroids, vitamins and the like, are concerned, the conventional modes of administration which allow continuous drug release are not always appropriate, since, in living organisms, said substances are to be released in a pulsating or pulse-like manner and living organisms have a function to suppress effect of such substance in case of giving them from inside or outside over the physiological level.
For example, it is known that luteinizing hormone (LH) is secreted in ovarectomized rhesus monkeys at about 60-minute intervals [Endocrinology, 87, 850-853 (1970)] and that, in rats, physiologically, growth hormone is secreted at intervals of about 3.5 hours [Endocrinology, 98, 562 (1976)]; it is also known that negative feedback is involved in the mechanisms of regulation of growth hormone (hGH) secretion, and it is reported that, in rats, administration of GH causes decreases in pituitary weight and GH content and an increase in somatostatin quantity in the hypothalamus [Life Sci., 24, 1589 (1979)]. Therefore, artificial continuous administration of such substances in large quantities is undesirable to living organisms in many cases.
Pulsewise administration of anticancer agents, antibiotics and the like is also desirable in certain cases. In particular, in the case of multiple drug therapy, pulsewise administration of several drugs differing in site of action in an effective order, for instance, can be expected to produce excellent effects in respect of efficacy, tolerance and reduced toxicity. From such viewpoint, pulsewise administration of drugs has been attempted.
Thus, for example, Langer et al. [J. Membrane Sci., 7, 333 (1980)] propose a pharmaceutical preparation for drug release by magnetic stirring, which comprises a drug substance and magnetic beads mixedly incorporated in a polymer (ethylene-vinyl acetate copolymer) matrix. Drug release is caused by vibrating the magnetic beads in the matrix by means of an external magnet. This preparation is indeed advantageous in that pulsewise drug release can be effected by actuating the external magnet intermittently, but the patient is restricted in his or her liberty by an external apparatus including said magnet. Moreover, continuous release at a certain rate is inevitable for structural reasons even when magnetic vibration is not effected, so that completely pulsewise release cannot be achieved.
Accordingly, an attempt has been made to attain liberation from external elements, decrease in complexity, and more complete pulsewise release. Thus, a sustained release composite preparation having a multi-layer structure as disclosed by Kaetsu et al. (specification of Japanese Patent Application laid open under No. 120618/81) can attain pulsewise drug release in an intrinsic and simple manner without using any external apparatus. Said preparation comprises alternatingly disposed drug-containing and drug-free layers, for example drug-containing layers and drug-free layers for envelopment of each drug-containing layer.
From the viewpoint of precise pulsewise release, however, such technique has room for improvement. There is a fear that in case of the sperical, cylindrical or sheet-type preparation, (disclosed in the specification of Japanese Patent Application laid open No. 120618/81) the release pulse becomes vague due to irregular erosion and diffusion.